) Background: Epidemiologic and experimental studies suggest that oral contraceptives (OCP) and fenretinide, N-(4hydroxypheny1) retinamide (4-HPR), may reduce the risk of developing epithelial ovarian cancer, but mechanisms underlying the chemopreventive activity of these agents remain unknown. Studies in primates and with human ovarian explants suggest that 4-HPR and progestins can induce TGF beta in stromal cells and apoptosis in the ovarian surface epithelium (OSE). Either 4-HPR or a combination of progestin and TGF beta can induce apoptosis in immortalized OSE (IOSE). 4-HPR can induce apoptosis in isolated normal OSE and this is enhanced with TGF beta. 4-HPR induces apoptosis in different tumor cell lines by generating reactive oxygen species or by binding to retinoic acid receptors. TGF beta and retinoids induce apoptosis by downregulating anti-apoptotic proteins. Hypotheses and Specific Aims: Based on these data, we will test the hypothesis that a combination of OCP and 4-HPR will induce apoptosis in a greater fraction of OSE than either agent alone, related in part to the production of TGF beta by ovarian stromal cells. We propose that 4-HPR induces apoptosis by stimulating production of reactive oxygen species, where as OCP components downregulate anti-apoptosis by stimulating production of reactive oxygen species, where as OCP components downregulate anti-apoptotoic proteins. TGF beta can augment apoptosis produced by 4-HPR or by progestin. In this portion of the SPORE we will (1) explore mechanisms underlying the chemopreventive activity of OCP and 4-HPR in OSE from women at normal and increased risk of ovarian cancer, (2) seek novel bio-markers for the impact of TGF beta on apoptosis induced by progestin, and (3) conduct a series of clinical trials to test the impact of OCP and an optimal dose of 4-HPR, individually and in combination, on induction of TGF beta in the stroma and apoptosis in the OSE of women at normal and increased risk of ovarian cancer. Significance: These studies may provide a rationale for the combined use of two promising agents for preventing ovarian cancer and elucidate mechanisms of their action.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
AACR Project GENIE Consortium (2017) AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov 7:818-831
Sans, Marta; Gharpure, Kshipra; Tibshirani, Robert et al. (2017) Metabolic Markers and Statistical Prediction of Serous Ovarian Cancer Aggressiveness by Ambient Ionization Mass Spectrometry Imaging. Cancer Res 77:2903-2913
Robertson, A Gordon; Shih, Juliann; Yau, Christina et al. (2017) Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. Cancer Cell 32:204-220.e15
Yeung, Tsz-Lun; Leung, Cecilia S; Wong, Kwong-Kwok et al. (2017) ELF3 is a negative regulator of epithelial-mesenchymal transition in ovarian cancer cells. Oncotarget 8:16951-16963
Gangwar, Ruchika; Meena, Avtar S; Shukla, Pradeep K et al. (2017) Calcium-mediated oxidative stress: a common mechanism in tight junction disruption by different types of cellular stress. Biochem J 474:731-749
Cho, Min Soon; Noh, Kyunghee; Haemmerle, Monika et al. (2017) Role of ADP receptors on platelets in the growth of ovarian cancer. Blood 130:1235-1242
Harjes, U; Bridges, E; Gharpure, K M et al. (2017) Antiangiogenic and tumour inhibitory effects of downregulating tumour endothelial FABP4. Oncogene 36:912-921
Sekihara, Kazumasa; Saitoh, Kaori; Han, Lina et al. (2017) Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1. Oncotarget 8:34552-34564
Yang, Wei-Lei; Gentry-Maharaj, Aleksandra; Simmons, Archana et al. (2017) Elevation of TP53 Autoantibody Before CA125 in Preclinical Invasive Epithelial Ovarian Cancer. Clin Cancer Res 23:5912-5922
Nagaraja, Archana S; Dood, Robert L; Armaiz-Pena, Guillermo et al. (2017) Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens. JCI Insight 2:

Showing the most recent 10 out of 625 publications